Prostate cancer is among the most frequent causes of cancer related mortality in men. There is a great demand for new and effective treatment, especially in hormone refractory late stage disease. Skeletal metastases are a frequent problem in late stage disease and therefore the alpha-particle emitter 223Ra (Xofigo) was introduced as a bone specific therapy for late stage prostate cancer patients with skeletal metastases.
Although, as a bone-seeker, 223Ra shows significant clinical benefit for patients its activity is limited to the bone metastases and is not targeting soft tissue metastases.
Several carrier molecules for radioligand targeting of prostate specific membrane antigen (PSMA) exists. Lutetium-177 labeled PSMA-617 (177Lu-PSMA-617) is the compound in most advanced clinical development stage for use in radionuclide therapy.
This molecule works in a suitable manner and give relevant tumor to normal tissue ratios for longer lived (i.e. a half-life of a few days) radionuclides, including 177Lu and 225Ac, but at early times points (typically a few hours after injection) shows high uptake in kidneys. With shorter lived radionuclides like 212Pb (half-life of 10.6 hours), the initial kidney uptake represents a potential toxicity problem.
It is therefore advantageous to use a PSMA-ligand with less kidney uptake, but this should not compromise the tumor uptake. The PSMA ligand molecules are made up of (1) a PSMA-binding region, (2) a linker region and (3) a chelator, whereby the linker region connects the (1) and (3). The linker region also is used to adjust molecular size and polarity etc to affect the in vivo distribution properties. The PSMA-binding region (motif) used in PSMA-617 is a structure that can be found in several molecules of this class, developed by several different inventors and researchers, including PSMA-11 and PSMA I&T as well as 131I and 211At labelled PSMA binding ligands.
New compounds that contain a PSMA region are warranted because at current all ligands in testing have challenges, including a relatively low radiobiological effectiveness (RBE) and suboptimal biodistribution.
There is also a need for an improved alpha emitter that can target both the bone metastases and the soft tissue metastases.
The present invention relates to compounds that addresses these challenges.